[Therapeutic adherence in asthma in France: A general review]. / L'adhésion thérapeutique dans l'asthme en France : revue générale.

INTRODUCTION: Adherence in asthma is a paramount issue of disease management. A general review of the French publications on this topic has been conducted. METHODS: Research equations used for bibliographic databases (MEDLINE, Science Direct, Banque de données en santé publique, Cochrane and Cairn.info) comprised the following keywords: "asthma", "therapeutic adherence" and "France". These publications unrelated to asthma, focused on asthma management without exploring adherence, or those conducted in populations without French patients were excluded. RESULTS: A total of 82 articles have been selected (36 surveys, 4 randomized trials and 42 reviews/syntheses). Whatever the methodology used and publication year, the inadequate therapeutic adherence in asthma was steadily reported, notably for controllers and the quality of use of inhaled devices. CONCLUSION: The present review highlights the sustainability of adherence-related issues in asthma and the need to improve patients' knowledge on asthma and the finality of therapy. It also highlights the need of an improved communication between patients and physicians is also advocated. Further studies with more recent data are desirable to assess changes in disease management of asthma and the impact of potential future corrective interventions.

Costs of perennial allergic rhinitis and allergic asthma increase with severity and poor disease control.

BACKGROUND: Perennial allergic rhinitis (PAR) represents a global and public health problem, due to its prevalence, morbidity, and impact on the quality of life. PAR is frequently associated with allergic asthma (AA). Costs of PAR with or without AA are poorly documented. OBJECTIVE: Our study aimed to detail medical resource utilization (MRU) and related direct cost for PAR, with or without concomitant AA, in France. METHODS: Using Electronic Health Records (EHRs), we identified in 2010 two cohorts of PAR patients, based on General Practitioners' diagnoses and prescribing data, with and without concomitant AA. For each patient, the EHRs were linked to corresponding claims data with MRU and costs during years 2011 to 2013. Predefined subgroup analyses were performed according to severity of PAR and level of AA control. RESULTS: The median annual cost reimbursed by social security system for a patient with PAR, and no AA was 159€ in 2013. This varied from 111€ to 188€ depending on PAR severity. For patients with PAR and concomitant AA, the median annual cost varied between 266€ and 375€, and drug treatment accounted for 42-55% of the costs, depending on asthma control. CONCLUSION: This study linking diagnoses from EHRs to claims data collected valid information on PAR management, with or without concomitant AA, and on related costs. There was a clear increase in costs with severity of PAR and control of AA.

[Deliberate interruptions and changes of dose of inhaled corticosteroids by asthma patients: "a community pharmacy study"]. / Interruptions et changements de posologie des corticoïdes inhalés par les patients asthmatiques: "enquête en pharmacie ".

BACKGROUND: Adherence to inhaled corticosteroids (ICS) remains a major issue for asthma management, even among patients receiving a regular prescription from their doctor. The frequency of deliberate interruption of ICS, and of spontaneous changes of dose, were studied in a population of asthma patients recruited in community pharmacies. METHODS: Asthma patients (aged 18-50) recruited in community pharmacies reported in self-administered questionnaires their spontaneous interruptions and changes of doses of ICS during the past 3 months. The characteristics of patients who interrupted their therapy or who modified the dose were compared with other patients. RESULTS: The studied population included 252 patients (mean age 35 year-old, females: 59%), of whom 62% had inadequately controlled asthma. Among these patients, 25% had interrupted ICS therapy during the past 3 months, while 21% spontaneously changed the dose. The most reported reason for interrupting ICS was the cessation of symptoms (50%). In multivariate analysis, interrupting ICS was mainly associated with inadequate asthma control (OR=3.1, 95% CI 1.5-6.4), while the strongest association with changing ICS doses was the patients' perception of asthma as a concern in their lives (OR=3.2, 95% CI 1.2-8.4). CONCLUSION: These results underline a poor understanding of the purpose of ICS therapy by patients. They also highlight the need of therapeutic education to improve the management of the disease.

Earlier disability of the patients followed in Multiple Sclerosis centers compared to outpatients.

OBJECTIVE: The currently published works regarding the multiple sclerosis (MS) natural history report data were collected most often on population of patients recruited in MS centers. The aim was to compare the natural history of a population of patients followed in a MS centre (MSC) with patients followed outside a MS centre (NMSC). METHODS: Cases were identified through the LORSEP cohort, a network of neurologists (private ambulatory practice, hospitals, and MS centers) in France. RESULTS: A total of 3602 patients had been analyzed: 1036 MSC patients and 2566 NMSC patients. No difference was observed regarding gender and initial symptoms. Conversely, MSC patients were younger at MS onset and were more likely to have a primary progressive initial form. Median times (years) to the EDSS scores of 3, 4, and 6 were 5.8 (5.0-6.8), 8.4 (7.9-9.0), 16.0 (14.8-18.1) in the MSC group, respectively, whereas corresponding times were 8.4 (7.9-9.0), 12.3 (11.4-13.4), 19.1 (18.0-20.2) in the NMSC group. These differences according to the type of MS supervision were statistically significant for EDSS3 (P < 0.0001), EDSS4 (P < 0.0001), and EDSS6 (P = 0.01), respectively. These findings were confirmed in Cox multivariate models. CONCLUSIONS: The patients followed in a MS centre had earlier disability than patients managed otherwise. Analyses exclusively conducted in patients with MS supervised in specialized centers may falsely misestimate the times needed to reach major disability landmarks. Before using registries to study the natural history of MS, efforts should be performed to verify in how far data are exhaustive and to understand the local health care system.

Galectin-10 mRNA is overexpressed in peripheral blood of aspirin-induced asthma.

BACKGROUND: In sensitive patients, aspirin is associated with nasal and bronchial inflammation, eliciting local symptoms. Although the disease is clinically well characterized, its physiopathology is incompletely understood and noninvasive procedures, allowing an effective distinction between aspirin-induced asthma (AIA) and aspirin-tolerant asthma (ATA) are missing. OBJECTIVES: The aims of the study were to compare AIA and ATA cohorts for clinical characteristics and to screen peripheral blood for differential mRNA expression. METHODS: Patients experiencing symptoms following aspirin ingestion were considered as aspirin sensitive. Peripheral blood was collected to quantify mRNA expression, using microarray technology and quantitative RT-PCR. RESULTS: Data indicated that AIA and ATA share large number of similarities for clinical phenotype. Screening of mRNA expression using microarray showed an overexpression of galectin-10 mRNA in AIA (AIA/ATA ratio = 1.9, P < 0.05). Results were confirmed using qRT-PCR. A positive correlation was established between microarray and qRT-PCR results for galectin-10 mRNA expression (r = 0.92, P < 0.0001). Finally, qRT-PCR results were validated on a subset of asthmatics and controls, showing an increased expression of galectin-10 mRNA in AIA vs ATA (P < 0.001) and vs controls (P < 0.01). CONCLUSIONS: Our results demonstrate that AIA and ATA remain difficult to distinguish using clinical criteria. Employing two molecular biological methods, we demonstrate that galectin-10 mRNA is overexpressed in AIA, suggesting a novel candidate gene and a potentially innovative pathway for mucosal inflammation in aspirin intolerance.

Patient-reported adverse events under asthma therapy: a community pharmacy-based survey.

The characteristics of patients who report adverse events (AEs) attributed to asthma therapy have been little investigated. Asthma patients aged 18-50 years were surveyed in pharmacies. Patients completed a questionnaire linked to computerized records of dispensed medications. Patients reported all AEs that they attributed to asthma therapy. The correlates of reporting 2+ AEs were identified. Almost 59% of the 1,351 patients (mean age: 37, 56% females) attributed AEs to asthma therapy, and 35% at least two. Most common AEs included tiredness (21.8%) and palpitations (21.1%). Poor asthma control and perception of asthma as a handicap were the major correlates of reporting 2+ AEs (odds ratio (OR)=2.5, 95% confidence interval (CI)=[1.7-3.7] and OR=1.9, 95% CI=[1.4-2.5]). Other significant correlates included age >30 years, female gender, and receiving psychotropic therapy. Inadequate control may partly account for AEs attributed by patients to asthma therapy. Improving patients' education may help to improve acceptability of asthma therapy.

Medication use and disease control of asthmatic patients in Flanders: a cross-sectional community pharmacy study.

The aim of this study was to describe medication use and disease management of asthmatic patients and to evaluate the usefulness of the Asthma Control Test (ACT) in community pharmacies. In 54 Flemish community pharmacies 166 asthmatic patients were included in the study. At inclusion, the study persons completed a survey to assess subject characteristics, symptoms and asthma attacks, and peak expiratory flow (PEF) was measured. Furthermore, the actual level of asthma control was assessed by ACT, a clinically validated measure of asthma control. Prescribed medicine data of the patients were 1 year retrospectively analysed from the prescriptions. Mean age of the sample was 36.8 year, 23% were smokers. As maintenance treatment, 63% of the patients used a combination product containing an inhaled corticosteroid and a long-acting beta2-agonist in a single inhaler. According to ACT, 49.1% of the patients were insufficiently controlled. Only 4.9% of the patients had a maximal ACT score of 25, indicating complete asthma control; 46.0% of the study population obtained an ACT score between 20 and 24, meaning that their asthma is well controlled. In contrast, 30.7% of the patients had a score between 15 and 19, indicating uncontrolled asthma. In all, 18.4% obtained ACT scores of less than 15, meaning that their asthma was seriously out of control and necessitating referral to their general practitioner or lung specialist. Importantly, the correlation between the self-perceived level of asthma control and the objective assessment of the asthma control level was poor: 82.3% of the patients believed their asthma to be totally or well controlled, while this was the fact for only 50.9% of the patients. In conclusion, the ACT appears to be a useful tool to determine rapidly and accurately the level of asthma control in patients presenting at community pharmacies.

Management of asthma in patients supervised by primary care physicians or by specialists.

French asthma patients may be supervised by general practitioners (GPs) and/or specialists. Therefore, this study examined asthma management in patients exclusively supervised by specialists (SPE), GPs, (GP) and both (GP+SPE group), and compared the findings. Asthma patients were consecutively recruited in 348 pharmacies. Each patient completed a questionnaire providing data on personal characteristics, asthma management, perception of disease and asthma supervision. Asthma control was measured using the Asthma Control Test. Questionnaires were linked to computerised records of medications which had been dispensed before inclusion in the study. From the 1,256 patients (mean age = 36.1 yrs, 54.3% females), 11.4, 36.6, and 52.0% were placed in the SPE, GP, and GP+SPE groups, respectively. During the previous 4 weeks, most patients in the SPE group were properly controlled (52.2 versus 26.4 and 21.5% in GP and GP+SPE groups, respectively). The SPE group made more use of fixed combinations of long-acting beta agonist and inhaled corticosteroid, while receiving less short-acting beta agonists, antitussives and antibiotics. Striking differences in symptoms and asthma management were observed according to the type of asthma supervision. The current results strongly support the need to improve the management of asthma in primary care, and the coordination of care between general practitioners and specialists.

Long-term achievement of the therapeutic objectives of lipid-lowering agents in primary prevention patients and cardiovascular outcomes: an observational study.

AIMS: Lowering elevated cholesterol levels reduces cardiovascular (CV) morbidity and mortality. Nonetheless, most patients treated with lipid-lowering agents (LLA) do not reach recommended therapeutic objectives. In a setting of primary care in France, we investigated the association between LDL-cholesterol goal attainment and the occurrence of CV events in primary prevention patients with multiple CV risk factors (> or = 3). According to national guidelines, the therapeutic objective (TO) for such patients is an LDL-cholesterol value below 130 mg/dL. METHODS: 579 patients treated with LLA and with LDL-cholesterol values documented at least once a year over a period of at least 3 years (2000-2002) were allocated to three groups based on the number of years the TO was attained during the follow-up period: in all 3 years (TO+++: n=145), only part of the time (TO intermediate: n=256), and never (TO---: n=178). CV events (angina pectoris, myocardial infarction, heart failure, stroke, peripheral artery disease) occurring during the last year of observation (2002) were retrospectively collected. The occurrence risk (OR) of CV events was assessed based on TO status, with a logistic regression model to adjust for baseline differences in CV risk factors. RESULTS: Only a quarter of patients attained TO during all 3 study years. CV events during the third year of observation occurred in 5.5%, 10.5% and 12.9% of patients in the TO+++, TO intermediate and TO--- groups, respectively. Compared with TO+++ patients, the risk of CV events increased significantly in TO intermediate (OR=2.34, 95% CI=[1.01-5.39]) and TO--- patients (OR=2.99, 95% CI=[1.26-7.08]). CONCLUSION: In real practice, a prolonged attainment of TO is rarely observed in high CV risk patients treated with LLA as primary prevention. Therapeutic failure is related to an increased incidence of cardiovascular morbidity. Our data strongly support the need to improve adherence to treatment guidelines to achieve effective cardiovascular prevention.

Asthma-related resource use and cost by GINA classification of severity in three European countries.

BACKGROUND: This study assessed the relationship between asthma burden and asthma severity in France, Italy, and Spain. METHODS: Adult asthmatics, 18-55 years of age, completed a questionnaire while visiting a respiratory physician in 1998 and 1999. Asthma severity was categorized by physicians as intermittent, mild persistent, moderate persistent, or severe persistent according to Global Initiative for Asthma (GINA) guidelines. RESULTS: Totals of 282 patients in France, 500 in Italy, and 296 in Spain entered the study. There were few differences between the three countries in the asthma symptom burden. Most patients with persistent asthma had used inhaled corticosteroids in the previous 14 days. Unexpectedly, 35% (Italy) to 83% (Spain) of patients with intermittent asthma also had used inhaled corticosteroids. In Spain, visits to the emergency department were more frequent (OR 7.0, 95% CI 4.9-10.0 with Italy as reference) and the costs of emergency care in all asthma severity categories were up to 10 times higher than in Italy and France. The frequency of hospitalizations did not differ systematically between the three countries. CONCLUSIONS: Inadequate control of asthma symptoms among patients with severe persistent asthma could not be entirely explained by under-prescribing of asthma medications. The use of inhaled corticosteroids by patients with intermittent asthma might reflect misclassification of asthma severity, possibly due to difficulty in interpreting the GINA guidelines. The relatively high cost of emergency care in Spain does not appear to be related to greater asthma severity or poorer symptom control, but may be a feature of the Spanish health care system.

Quality of asthma care: results from a community pharmacy based survey.

BACKGROUND: Optimal control is a major objective of disease management of asthma. The aim of the present study was to provide descriptive data on disease management in asthma patients, including medical resource utilization. METHODS: Asthma patients (age 18-50 years) were consecutively recruited in 348 dispensing pharmacies. They completed a questionnaire which collected data on personal characteristics, asthma management, including medical resource utilization, including asthma management. Asthma control was measured with the Asthma Control Test. Data from computerized pharmacy records of medications, dispensed before inclusion, were also collected. RESULTS: In 1791 eligible patients, 1559 accepted to participate in the study (mean age = 36.5, 56.1% of females). During the previous 4 weeks, the asthma control was satisfactory for only 28% of the patients, despite extensive provision of anti-inflammatory asthma control treatments (89%). Combinations of long acting beta agonists (LABA) and inhaled corticosteroids (ICS) were commonly used (59%), while fewer patients received LABA and ICS as two separate medications (15%). In addition, short-acting beta agonists, were frequently dispensed (71%). A substantial number of patients consulted their GPs on a monthly basis. Patients commonly reported daily shortness of breath (30%), daily use of rescue medication (29%) and weekly nocturnal symptoms (32%). Surprisingly, most patients considered their asthma as completely or well controlled (76%). CONCLUSIONS: Our results clearly identify a need to improve the management of asthma. Education programmes would be beneficial to improve asthma control.

Ineffectiveness of lipid-lowering therapy in primary care.

BACKGROUND: Evidence confirms the positive effects of lipid-lowering agents on the risk of cardiovascular disease. Local guidelines in France (AFSSAPS) have defined therapeutic objectives for LDL-cholesterol. These objectives vary with the number of cardiovascular risk factors in addition to dyslipidaemia. We determined the proportions of patients at therapeutic objective in different classes of cardiovascular risk to test the hypothesis that compliance with guidelines varies across the levels of risk. Comparison with international guidelines (ANDEM) was also performed. METHODS: A group of 3173 dyslipidaemic patients treated with lipid-lowering agents and managed by general practitioners was randomly selected from BKL-Thales panel, a French computerized database. For each patient, history of coronary heart disease and the number of cardiovascular risk factors were documented. Compliance with guidelines was assessed from achievement of therapeutic objective. RESULTS: The study population included 79% primary prevention patients (1.6, 25.5, 31.7 and 20.1%, with 1, 2, 3, and >3 risk factors, respectively) and 21.0% secondary prevention patients. Applying AFSSAPS guidelines, the proportions of primary prevention patients not at LDL-cholesterol objectives varied across risk categories (P < 0.0001), from 3.9% for patients with one risk factor to 46.5% for patients with >3 risk factors, and therapeutic failure reached 39.9% in secondary prevention. Only 26% of patients who were at high cardiovascular risk (>3 risk factors or prior coronary heart disease) and not at therapeutic objective received high doses (>standard recommended doses) of lipid-lowering agents in monotherapy. Applying ANDEM guidelines, 74% of secondary prevention patients were not at treatment goal. CONCLUSION: Compliance with guidelines varied inversely with the level of cardiovascular risk. Besides, most patients not at therapeutic objective were not up-titrated. The use of lipid-lowering agents is inadequate, depriving many patients of an effective protection against cardiovascular diseases.

[Is there an interaction between sleep-disordered breathing, depression and apolipoprotein E phenotype?]. / Existe-t-il une relation entre syndrome d'apnées du sommeil, dépression et phénotype de l'apolipoprotéine E?

Sleep-disordered breathing (SDB) is widely underdiagnosed among adults. However, SDB may be considered as a public health problem because of clinical consequences for the patient: impaired awake performance, increased risk factor for cardiovascular diseases and increased prevalence of depression. Apolipoprotein E (apoE), a protein involved in lipid metabolism, has 3 major alleles e2, e3 and e4. Recently, it has been shown that apoE e4 allele, a well-known risk factor for cardiovascular diseases, was also associated with SDB. In this study, we assessed a potential interaction between SDB, depression and apoE phenotype. 92 male patients (36-79 years old, mean age 58.0 11.2) consulting in hospital for SDB were enrolled in the study. Each patient had the following exams: 1) overnight polysomnography to determine apnea/hypopnea index (AHI=average number of respiratory events 10 seconds with no breathing per hour). A moderate-to-severe SDB was defined with AHI 15. 2) a psychiatric examination to look for previous or present symptoms of depressive illness. 3) blood sampling to determine apoE genotype (using PCR-RFLP method). In our study, allele frequencies for apoE e2, e3 and e4 were similar to those reported in general population. Among 92 patients, 68 (74%) presented moderate-to-severe SDB and 28 (30%) previous or present symptoms of depressive illness. Our results indicate that: 1) apoE e4 was significantly associated with moderate-to-severe SDB (n=92, p=0.03), 2) scores of apnea-hypopnea index were significantly higher in e4-positive versus e4-negative participants (n=57, p=0,05) and 3) ApoE and depression were not linked. This study confirms a potential interaction between SDB and apoE phenotype, as recently reported. This suggests that e4 allele might be a genetic risk factor for SDB (e4 allele frequency higher in patients with moderate-to-severe SDB versus general population) and/or consequently a deleterious factor for this pathology (increased AHI in e4-positive versus e4-negative patients). Depression might be only one of clinical consequences of SDB. Thus, SDB leads to repeated hypoxemia and numerous awakenings resulting in fatigue and decreased cognitive abilities suitable to the onset of depressive illness in vulnerable persons.

Persistent asthma: disease control, resource utilisation and direct costs.

Despite evidence that adverse outcomes are less frequent when asthma management is optimised, the link between the level of control, disease severity and medical resource utilisation (MRU) is poorly documented. This relationship was investigated in a group of patients suffering from persistent asthma (Global Initiative for Asthma (GINA) > or = 2) in France. In 1998 a computerised family practice database was used to identify asthma patients aged 17-50 yrs. Information from the database was complemented by a patient survey to retrospectively assess the level of asthma control and hospital contacts. Costs of MRU over a 12-month study period were related to demographics, medical history, asthma control, and doses of inhaled corticosteroids prescribed during the prestudy period. A review of the computerised medical database identified 1,038 adult patients with persistent asthma, who completed the survey questionnaire. Over a 12-month period, the mean cost of MRU was 549.8 euros for well-controlled patients, 746.3 euros per patient with moderate control, and 1,451.3 euros per patient with poor control. Costs also increased significantly with age, access to free asthma care, comorbid conditions, asthma symptoms in the past year and whether inhaled corticosteroids had been prescribed before the study period. In patients with persistent asthma, large differences were observed in the use of medical resources according to control and severity. Therefore, if patients appropriately use prescribed control therapy, their use of medical resources may be reduced.

Occupational risk factors, ultraviolet radiation, and ocular melanoma: a case-control study in France.

BACKGROUND: Ultraviolet radiation has been suspected as a possible cause of ocular melanoma. Because this association is controversial, we examine the role of occupational exposure to ultraviolet radiation on the occurrence of this rare cancer. MATERIAL AND METHODS: A population-based case-control study was conducted in 10 French administrative areas (départements). Cases were 50 patients with uveal melanoma diagnosed in 1995-1996. Controls were selected at random from electoral rolls, after stratification for age, gender, and area. Among 630 selected persons, 479 (76%) were interviewed. Data on personal characteristics, occupational history, and detailed information on each job held were obtained from face-to-face interviews using a standardized questionnaire. Estimates of occupational exposure to solar and artificial ultraviolet light were made using a job exposure matrix. RESULTS: Results show elevated risks of ocular melanoma for people with light eye color, light skin color, and for subjects with several eye burns. The analysis based on the job exposure matrix showed a significantly increased risk of ocular melanoma in occupational groups exposed to artificial ultraviolet radiation, but not in outdoor occupational groups exposed to sunlight. An elevated risk of ocular melanoma was seen among welders (odds ratio = 7.3; 95% confidence interval = 2.6-20.1 for men), and a dose-response relationship with job duration was observed. The study also showed increased risk of ocular melanoma among male cooks, and among female metal workers and material handling operators. CONCLUSION: Following the present study, the existence of an excess risk of ocular melanoma in welders may now be considered as established. Exposure to ultraviolet light is a likely causal agent, but a possible role of other exposures in the welding processes should not be overlooked.

Cell proliferation and movement during early fin regeneration in zebrafish.

Cell proliferation and cell movement during early regeneration of zebrafish caudal fins were examined by injecting BrdU and Di-I, respectively. In normal fins of adult fish, a small number of proliferating cells are observed in the epidermis only. Shortly following amputation, epithelial cells covered the wound to form the epidermal cap but did not proliferate. However, by 24 hr, epithelial cells proximal to the level of amputation were strongly labeled with BrdU. Label incorporation was also detected in a few mesenchymal cells. Proliferating cells in the basal epithelial layer were first observed at 48 hr at the level of the newly formed lepidotrichia. At 72 hr, proliferating mesenchymal cells were found distal to the plane of amputation whereas more proximal labeled cells included mainly those located between the lepidotrichia and the basal membrane. When BrdU-injected fins were allowed to regenerate for longer periods, labeled cells were observed in the apical epidermal cap, a location where cells are not thought to proliferate. This result is suggestive of cell migration. Epithelial cells, peripheral to the rays or in the tissue between adjacent rays, were labeled with Di-I and were shown to quickly migrate towards the site of amputation, the cells closer to the wound migrating faster. Amputation also triggered migration of cells of the connective tissue located between the hemirays. Although cell movement was induced up to seven segments proximal from the level of amputation, cells located within two segments from the wound provided the main contribution to the blastema. Thus, cell proliferation and migration contribute to the early regeneration of zebrafish fins.

Laryngeal and hypopharyngeal cancers and occupational exposure to formaldehyde and various dusts: a case-control study in France.

OBJECTIVES: A case-control study was conducted in France to assess possible associations between occupational exposures and squamous cell carcinomas of the larynx and hypopharynx. METHODS: The study was restricted to men, and included 201 hypopharyngeal cancers, 296 laryngeal cancers, and 296 controls (patients with other tumour sites). Detailed information on smoking, alcohol consumption, and lifetime occupational history was collected. Occupational exposure to seven substances (formaldehyde, leather dust, wood dust, flour dust, coal dust, silica dust, and textile dust) was assessed with a job exposure matrix. Exposure variables used in the analysis were probability, duration, and cumulative level of exposure. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were estimated by unconditional logistic regression, and were adjusted for major confounding factors (age, smoking, alcohol, and when relevant other occupational exposures). RESULTS: Hypopharyngeal cancer was found to be associated with exposure to coal dust (OR 2.31, 95% CI 1.21 to 4.40), with a significant rise in risk with probability (p<0.005 for trend) and level (p<0.007 for trend) of exposure. Exposure to coal dust was also associated with an increased risk of laryngeal cancer (OR 1.67, 95% CI 0.92 to 3.02), but no dose-response pattern was found. A significant relation, limited to hypopharyngeal cancer, was found with the probability of exposure to formaldehyde (p<0.005 for trend), with a fourfold risk for the highest category (OR 3.78, 95% CI 1.50 to 9.49). When subjects exposed to formaldehyde with a low probability were excluded, the risk also increased with duration (p<0.04) and cumulative level of exposure (p<0.14). No significant association was found for any other substance. CONCLUSION: These results indicate that exposure to formaldehyde and coal dust may increase the risk of hypopharyngeal cancer.

CYP2D6 gene polymorphism in caucasian smokers: lung cancer susceptibility and phenotype-genotype relationships.

Individual susceptibility to smoking-related cancers is proposed to partly depend on a genetically determined ability to metabolise tobacco carcinogens. We previously reported on the association between the activity of the xenobiotic-metabolising enzyme CYP2D6 and lung cancer risk in a hospital-based case-control study among French Caucasian smokers. Here we extended the study to address the effect of four gene-inactivating mutations (CYP2D6(*)3, (*)4, (*)5 and (*)16) and the gene duplication of the CYP2D6 gene (CYP2D6(*)2x2 or CYP2D6(*)1x2) on lung cancer risk in the same population (150 patients with primary lung carcinoma of squamous cell or small cell histology and 172 controls). The risk of lung cancer associated with the CYP2D6 poor metaboliser genotype (odds ratio 1.5, 95% confidence interval 0.5-4.3) did not differ from that in the reference category of extensive metaboliser and ultra-rapid metaboliser genotypes combined. Lung cancer risks for the CYP2D6 PM genotype amongst light smokers (tobacco consumption 20 g/day) were not significantly different. The present findings agree with the discrepancy between the phenotype-based and genotype-based studies indicated by the recent meta-analyses.